Abstract 3238: Synthesis and evaluation of 17-oximino-estrone derivatives as potential anti-breast cancer agents

Abstract

Abstract The selective estrogen receptor modulator (SERM) tamoxifen (TAM) is the gold standard used in the treatment of estrogen-dependent breast cancer. Although it significantly benefited women with breast cancer, time-dependent tumor resistance and the risk of endometrium cancer are associated with it. Consequently, there is an urgent need for alternative treatments. PURPOSE: Incorporating the oxime moiety in conjunction with various basic side chains associated with the pharmacophore of the SERMs into estrone may yield various estrone derivatives with antiestrogenic activity. The estrone derivatives were compared to 4-hydroxy-tamoxifen (4-OH-TAM) and raloxifene (RAL). METHODS: The estrone derivatives were synthesized using established chemical procedures. The Southern Research Institute in Birmingham, Alabama carried out the cytotoxicity studies in MCF-7, MDA-MB-231 and Ishikawa cancer cells. They tested different concentrations of the six different estrone derivatives ranging from .01 nM to 100,000 nM on 5000 MCF-7 cells/well, on 5000 MDA-MB-231 cells/well and on 5000 Ishikawa cells/well. Cells pre-treated with the various estrone derivatives were incubated at 37°C for 3 days followed by MTS assay. Their IC50 values were generated using GraphPad Prism 5.0. RESULTS: Our compounds demonstrated anti-proliferative activity in MCF-7 cells but they were not as potent as 4-OH-TAM(2µM) or RAL (3µM). Compounds 2, 3, 4, 6, and 7 (31µM, 29µM, 30µM, 30µM, and 29µM respectively) were comparable in potency to RAL (28µM) in MDA-MB-231 cells but all were not as potent as 4-OH-TAM (22µM). Compounds 3, 6, and 7 (20µM, 20µM, and 17µM respectively) were comparable or greater in potency to 4-OH-TAM (20µM) in Ishikawa cells and compounds 2, 3, 6, and 7 (24µM, 20µM, 20µM, and 17µM respectively) were comparable or greater in potency to RAL (23µM). CONCLUSION: Applying the oxime moiety in conjunction with the pharmacophore of the SERMs to estrone produced agents with antiproliferative activity. They also showed antiproliferative activity in estrogen-receptor negative MDA-MB-231 cells. These results suggest that several of the estrone derivatives show promise as potential anti-breast cancer agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3238. doi:10.1158/1538-7445.AM2011-3238